Much data suggests that in Alzheimer disease (AD) there may be genetically and/or environmentally induced defects in the enzymatic machinery involved in degradation of amyloid precursor protein (APP) (for reviews, see refs. 1 and 2). Alternative splicing of mRNAs gives rise to at least five forms of APP, two of which possess a Kunitz-type protease inhibitory domain. Normal lysosomal processing of APPs involves highly coordinated sequences of desulfation, dephosphorylation, deglycosylation, and proteolytic splitting. The APPs may belong to a family of polypeptide precursors or polyproteins that upon processing give rise to a number of different bioactive peptides that may act individually or in concert to regulate cellular activation (3-5). The processing of the parent molecules and/or the extracellular secretion of the resulting subunits may vary with species, tissue, age, hormonal status, extent of phosphorylation (6), etc. Although the APPs may be cell-surface receptors (7, 8), some of the peptidic fragments derived from them may be ligands (9) for specific membrane sites.
To some extent in normal aging and to greater extent in AD and in adult Down syndrome, abnormal processing of APP gives rise to an insoluble self-aggregating 42-amino acid polypeptide designated as amyloid .beta. protein (A.beta.) that is found in amyloid (10-14). The extent of A.beta. deposition correlates with the degree of neuronal damage, cognitive impairment, and memory loss (15-18). Amyloid-like fibrils arise readily in vitro under physiological conditions even from the following smaller peptides homologous to A.beta.: .beta.-(1-28) (N-terminus residues 1 to 28), [Gln.sup.11 ].beta.-(1-28), .beta.-(12-18), and .beta.-(18-28) (19-21). Extensive stacks of .beta.-pleated sheets are formed from the latter peptide (21). Functional deficits arise in AD from damage to nerve circuitry per se, which is known to occur in late phases of the disease (22, 23). It also is possible that binding of A.beta. and related peptides to components of the extracellular matrix (e.g., proteoglycans (24)) or to receptors on endothelial, glial, or neuronal cells in particular brain regions could have disruptive effects on neuronal communications at earlier stages of the disease when the deposits of these substances are diffused and typical cytopathologiocal evidence of AD often is absent.
It has been demonstrated (25) that A.beta. and, perhaps, smaller peptidic fragments thereof that are responsible for binding of A.beta. to cell membranes or components of the extracellular matrix may have amnestic effects upon appropriate administration to experimental animals. Hence, soluble peptides or structurally mimetic nonpeptidic substances can be devised to antagonize the binding of the A.beta. and thus alleviate some of the symptoms of AD not caused b actual physical destruction of neural circuitry. Progression may also be attenuated by such substances.